Journal Article

Inhibitory effects of mofezolac, a cyclooxygenase-1 selective inhibitor, on intestinal carcinogenesis

Tomohiro Kitamura, Toshihiko Kawamori, Naoaki Uchiya, Masaki Itoh, Tetsuo Noda, Mamoru Matsuura, Takashi Sugimura and Keiji Wakabayashi

in Carcinogenesis

Volume 23, issue 9, pages 1463-1466
Published in print September 2002 | ISSN: 0143-3334
Published online September 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.9.1463
Inhibitory effects of mofezolac, a cyclooxygenase-1 selective inhibitor, on intestinal carcinogenesis

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Cyclooxygenase (COX)-2, one enzyme isoform responsible for producing prostanoids from arachidonic acid, contributes to colon carcinogenesis. Recently, genetic disruption of COX-1, the other isoform, was shown to decrease the number of intestinal polyps and prostaglandin E2 levels in intestinal mucosa, like the case with COX-2 gene disruption, in Min mice. We therefore investigated whether a COX-1 selective inhibitor, mofezolac, suppresses intestinal carcinogenesis in rodents. F344 male rats, receiving azoxymethane (AOM, 15 mg/kg body wt) s.c. injections at 5 and 6 weeks of age, were fed a diet containing 600 or 1200 p.p.m. mofezolac for 4 weeks. The number of aberrant crypt foci (ACFs) per rat and the bromodeoxyuridine labeling index of the crypt epithelium were dose-dependently decreased by administration of mofezolac, the value for the former at 1200 p.p.m. being 60% of control value. When Apc gene knockout mice (APC1309 mice) were given 600 or 1200 p.p.m. mofezolac in their diet for 8 weeks, the numbers of intestinal polyps were also dose-dependently decreased, with reduction to 59% of that in the control diet group at the higher dose. Nimesulide, a COX-2 selective inhibitor used as positive control, showed similar suppressive effects on the development of ACFs in AOM-treated rats and polyps in Apc gene knockout mice. The data indicate that both COX-1 and COX-2 can contribute to intestinal tumorigenesis.

Keywords: AOM, azoxymethane; ACs, aberrant crypts; ACFs, aberrant crypt foci; Apc, adenomatous polyposis coli; BrdU, bromodeoxyuridine; COX, cyclooxygenase; FAP, familial adenomatous polyposis; NSAIDs, non-steroidal anti-inflammatory drugs; PGE2, prostaglandin E2

Journal Article.  3376 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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